ABSTRACT:Hyponatremia,
the most commonly encountered electrolyte disorder in clinical
practice, is associated with increased mortality. This harmful medical
comorbidity is often overlooked and untreated in psychiatric patients.
In these particular patients, hyponatremia is associated with
psychogenic polydipsia. Successful treatment depends upon accurate
diagnosis of the severity and underlying etiology along with appropriate
tests and monitoring. Hyponatremia induced by SIADH (syndrome of
inappropriate antidiuretic hormone secretion) and psychogenic polydipsia
require significant pharmacist interventions and are frequently seen in
psychiatric patients.

Hyponatremia, defined as serum sodium (Na+) <136
mmol/L, is the most commonly encountered electrolyte disorder in
clinical practice and is associated with increased mortality.1,2 In addition, hyponatremia is a frequently undiagnosed and untreated medical comorbidity in psychiatric patients.3,4
Successful treatment of hyponatremia depends upon accurate diagnosis of
the severity and underlying etiology along with the appropriate tests
and monitoring.5

Classification

Hyponatremia presents as hypertonic or hypotonic; however,
only hypotonic hyponatremia is of clinical relevance. Hypertonic
hyponatremia is often due to a laboratory error caused by marked
elevations of lipids or plasma proteins (pseudohyponatremia) or to a
marked increase in plasma glucose.6 Hypotonic hyponatremia is
categorized by severity and volume status. Severity of hyponatremia is
classified as acute or chronic, differentiated by sodium levels and
patient symptoms.7 Mild-to-moderate hyponatremia is a more
chronic and asymptomatic condition and is defined as a sodium
concentration of 120 to 135 mEq/L.7 Severe hyponatremia is a
medical emergency and is usually defined as a sodium concentration of
<120 mEq/L or hyponatremia with symptoms that may include seizures,
coma, and respiratory arrest.7

After severity is assessed, the patient’s volume status is
classified as hypervolemic (increased total body water), euvolemic
(increased total body water but not clinically significant on physical
examination), or hypovolemic (low total body water). This discussion
will focus primarily on euvolemic hyponatremia induced by SIADH
(syndrome of inappropriate antidiuretic hormone secretion) and
psychogenic polydipsia.

Epidemiology

Hyponatremia is seen in about 4% of patients with chronic
schizophrenia and occasionally in patients with other psychiatric
disorders.2 Primary polydipsia is prominent in patients with
psychosis, affecting nearly 7% of patients with schizophrenia. In
addition to the underlying psychosis, psychotropic drugs may cause the
sensation of a dry mouth, which may contribute to increased water
intake.8 Thus, causality between psychotropic agents and
hyponatremia has been shown more persuasively with antidepressants and
mainly with selective serotonin reuptake inhibitors (SSRIs). The
incidence of hyponatremia caused by SSRIs varies widely, from 0.5% to
32%.4 In the majority of cases, hyponatremia occurs within
the first few weeks of the onset of therapy, whereas normonatremia is
achieved within 2 weeks after drug withdrawal.4

Hyponatremia caused by SIADH is due to increased release
of antidiuretic hormone (ADH). SIADH has been associated with many drugs
often used in psychiatric patients, including nicotine, barbiturates,
carbamazepine, antipsychotics, and antidepressants.9

Pathophysiology

The mechanism by which hyponatremia develops varies
according to disease state, and arginine vasopressin (AVP) regularly
plays a critical role in both hypervolemic and euvolemic hyponatremia.
In healthy individuals, the mechanism for free water excretion is due to
AVP suppression caused by a fall in plasma osmolality.10
However, patients with hyponatremia are unable to suppress AVP due to
true volume depletion, effective volume depletion, or an inappropriate
increase in AVP secretion.11,12 AVP is produced in the
hypothalamus and then transported and stored in the posterior pituitary
gland. Physiologically, AVP targets three receptors, V1A (vascular), V2
(kidney), and V3 (pituitary).10 Antagonizing the V2 receptors in the kidney promotes aquaresis (elimination of solute free water).13 In SIADH, AVP release is increased despite plasma osmolality, which can be due to various medications (TABLE 1).14-17In
hypervolemic hyponatremia induced by congestive heart failure (CHF),
the reduction in cardiac function causes ineffective arterial
circulation; therefore, AVP is upregulated to induce cardiomyocyte
hypertrophy and vasoconstriction via V1A and to enhance renal water
retention via V2 as compensatory mechanisms. In cirrhosis-induced
hypervolemic hyponatremia, the reduced arterial pressure is due to
peripheral vasodilation resulting in low intravascular oncotic pressure,
which causes an upregulation of AVP receptors.13

The pathogenesis of psychogenic polydipsia is
multifactorial, with an abnormal hypothalamic thirst center as a likely
cause. Patients tend to have a difference in the set points of ADH and
thirst suppression. They present with polydipsia even when ADH is fully
suppressed.18

Alcohol abuse is common in psychiatric patients, and often
these patients present with hyponatremia. Beer drinkers (potomania) and
other malnourished patients often have reduced ability to excrete free
water based on low solute intake.19 In order to maximize the
kidney’s ability to excrete free water, a basic level of solute intake
is required. The result is markedly impaired free water excretion. Such
patients develop hyponatremia with low urine osmolality (<100
mOsm/kg).19

Diagnosis and Assessment

The fundamental criteria considered when diagnosing
hyponatremia are plasma osmolality, urinary electrolytes, volume status,
fractional excretion of sodium (FeNa), and the ability to rule out
hypothyroidism and glucocorticoid deficiency.20

Hypovolemic hyponatremia is usually seen in patients
presenting with severe diarrhea or vomiting and urine sodium values
<30 mmol/L.6 In euvolemic patients, hyponatremia is most
often due to SIADH, and patients typically have urine sodium levels
>40 mEq/L. Patients presenting with SIADH are usually asymptomatic
unless the sodium level is below 120 mEq/L.7 Free water excretion is impaired in SIADH, as evidenced by urine osmolality levels >100 mOsm/kg.12

SIADH is often a diagnosis of exclusion. When
differentiating between SIADH and psychogenic polydipsia, it is
important to measure serum sodium, osmolality, and urine osmolality (TABLE 2).21
Early diagnosis and monitoring of symptoms are important for reducing
the morbidity and mortality associated with hyponatremic encephalopathy.6 Patients with psychogenic polydipsia may present with impaired mental status and further exacerbation of psychiatric symptoms.22 Patient symptoms may include urinary incontinence, including enuresis.21

Treatment

The treatment of hyponatremia involves the removal of free water, treatment of underlying causes, and use of saline infusion.23 Treatment is further strategized by the severity, which depends on the sodium level, time to development, and patient symptoms.7
Treatment of severe hyponatremia should take place in a critical care
setting with isotonic or hypertonic fluids and frequent monitoring of
serum sodium in order to ensure a safe rate of sodium correction.1,7
Treatment of mild-to-moderate hyponatremia should focus on treating the
underlying cause, and further therapy considerations are dependent on
the etiology.

An important clinical pearl is to correct the sodium level
by no more than 12 mEq/L in 24 hours or 18 mEq in 48 hours. This is
done in order to prevent the life-threatening complication known as osmotic demyelination syndrome (ODS), which is characterized by cerebral edema.24

Hypervolemic Hyponatremia:In the
treatment of hypervolemic hyponatremia, water restriction is recommended
as first-line therapy. Other therapies include diuretic therapy with
furosemide, sodium restriction, or initiation of vaptan therapy. Current
literature supports water restriction from 800 to 1,200 mL in 24 hours.7
If sodium and water restriction and the use of diuretics have not
adequately corrected the sodium levels, it is then reasonable to
initiate vaptan therapy in hypervolemic hyponatremia induced by CHF or
cirrhosis.

Euvolemic Hyponatremia:Euvolemic
hyponatremia caused by thiazide diuretics, SIADH, or psychogenic
polydipsia requires the most pharmacist intervention. A recent clinical
trial showed that 8.5% of patients presenting to the emergency room used
one diuretic, 2.5% used two, and 0.4 % used three or four, and of
those, 4% had hyponatremia on admission.25

Thiazide-induced hyponatremia occurs most frequently in elderly woman and usually develops within 2 weeks of therapy initiation.16
Thiazide diuretics cause hyponatremia by blocking sodium reabsorption
in the distal tubule and causing proportionally more sodium loss than
water. Treatment involves discontinuing thiazide diuretic therapy.
Pharmacists play a key role in identifying thiazide-induced hyponatremia
and ensuring that there is proper documentation and that reinitiation
of thiazide therapy does not occur in the future.16

Pharmacists also play an important role in recognizing which drugs cause euvolemic hyponatremia induced by SIADH (see TABLE 1).14-17
Management of drug-induced SIADH involves removal of the offending
agent and providing supportive care based on the severity of
hyponatremia. Treatment of chronic asymptomatic hyponatremia induced by
SIADH includes removal of the offending agent, water restriction, and
then consideration of the initiation of vaptan therapy. Other
pharmacologic options include demeclocycline, lithium, and urea.6
The use of these drugs is currently limited in practice due to their
adverse-effect profiles, including renal toxicity. Of these agents,
demeclocycline is best tolerated, and if initiated should be dosed at
600 to 1200 mg/day in divided doses.6

With respect to SSRI-induced SIADH, cross-sensitivity among agents has been reported, but published data are scarce.17
A different SSRI may be initiated, but practitioners should be cautious
and monitor serum Na concentrations at baseline and 1 to 2 weeks after
initiation of therapy.17

With antipsychotics, it is important for healthcare
practitioners to differentiate between drug-induced SIADH and
psychogenic polydipsia. Current treatment of psychogenic polydipsia
includes reducing fluid intake, behavioral modification, and
pharmacologic therapy in an attempt to decrease thirst.6

Atypical antipsychotics such as clozapine and risperidone
have been shown to be effective in treatment of psychogenic polydipsia
in case reports.26,27 A study published in 2011 showed that
acetazolamide may also be an effective treatment option where 4 out of 5
patients treated with acetazolamide showed improved polydipsia and/or
hyponatremia.28

Hypovolemic Hyponatremia:Therapy for
hypovolemic hyponatremia involves treating the underlying cause and
initiating fluid replacement until the patient is clinically euvolemic.6
Normal saline (NS) is initiated unless the patient presents with
symptomatic hyponatremia in which hypertonic fluid (3% NS) is used.1

Vaptan Therapy:Vaptans are AVP receptor antagonists that are used for the treatment of hypervolemic and euvolemic hyponatremia.29
The FDA-approved vaptans are conivaptan (Vaprisol) and tolvaptan
(Samsca). Conivaptan is available in IV form and antagonizes V1 and V2
vasopressin receptors.30 The removal of free water happens by antagonizing the V2 receptors in the kidney.13,24
It is dosed at 20 mg IV once over 30 minutes, then 20 mg IV over 24
hours for 2 to 4 days. It is not advisable to use conivaptan for more
than 4 days and in patients with creatinine clearance (CrCl) <30
mL/min.30 Additionally, conivaptan should not be used in
patients with cirrhosis because of its inhibition of V1 receptors, which
could exacerbate splanchnic vasodilation and interfere with platelet
aggregation, promoting variceal bleeding.13,24,30 Conivaptan is a CYP3A4 enzyme inhibitor and therefore has many drug interactions.24 Pharmacists should educate prescribers on appropriate use of vaptans.

Tolvaptan is an FDA-approved oral vaptan.31 It
selectively binds to the V2 receptors of the distal nephron, promoting
the excretion of free water. Although it is an oral agent, tolvaptan has
to be initiated in an inpatient setting and then continued on an
outpatient basis.31 It is dosed at 15 mg daily and may be
increased to 30 mg after 24 hours, then to a maximum of 60 mg daily for
up to 30 days. Use should be avoided in CrCl <30 mL/min.32

In January 2013, the FDA published a new black box warning that tolvaptan is associated with a potential risk of liver injury.31
It is recommended that providers perform prompt liver tests in patients
who present with symptoms indicative of liver failure, including
fatigue, anorexia, right upper abdominal discomfort, or jaundice. If
hepatic injury is suspected, tolvaptan should be discontinued and
appropriate treatment of liver injury initiated. Tolvaptan should not be
reinitiated in these patients unless the cause of the liver injury was
determined to be unrelated to tolvaptan.31

Although vaptan therapy may be used for hypervolemic and
euvolemic hyponatremia, its use has not been shown to have any effect on
morbidity or mortality in clinical trials.33-38 These
medications are relatively expensive and require strict monitoring,
resulting in a potential burden on healthcare resources. Since vaptans
play a critical role in last-line treatment of hyponatremia, it is of
paramount importance that facilities ensure proper utilization and
monitoring of therapy.

Pharmacist’s Role and Conclusion

Careful observation is required to expedite the
recognition of hyponatremia across the spectrum of psychiatric
disorders. Compulsive water consumption may impair mental status and
further exacerbate psychiatric symptoms.22 Urinary incontinence, including enuresis, is a possible sign of underlying polydipsia.21 The measurement of serum osmolality is central to the assessment of a patient with documented hyponatremia.21
When a patient presents with these signs and symptoms, pharmacists can
intervene and rule out excessive water intake and medications associated
hyponatremia. When psychogenic hyponatremia is suspected, the
pharmacist can confirm causation by requesting a basic metabolic panel.
Thus, the pharmacist plays a vital role in the interdisciplinary team in
providing management of hyponatremia in psychiatric patients.

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